The invention relates to therapeutic quinolinone derivatives such as cilostazol and chemical intermediates useful for their preparation. The present invention also relates to 6-hydroxy-3,4-dihydroquinolinone, which is one such intermediate.
The present invention pertains to 6-hydroxy-3,4-dihydroquinolinone (xe2x80x9c6-HQxe2x80x9d) of formula (I) 
a known compound that is difficult to prepare on a large scale because of the sluggishness of the reaction by which it is prepared using conveniently accessible starting materials and because of the need to maintain a high reaction temperature throughout the reactor. 6-HQ has commercial importance as a key intermediate in the preparation of cilostazol.
Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone) is used to treat symptoms of intermittent claudication in patients suffering from symptoms of the disease, which include pain and cramping while walking due to reduced blood flow to the legs. Cilostazol has the chemical structure of formula (II). 
Cilostazol is described in U.S. Pat. No. 4,277,479, which teaches that it can be prepared by alkylating the phenol group of 6-HQ with a 1-cyclohexyl-5-(4-halobutyl)-tetrazole of formula (III). 
The first preparation of 6-HQ to appear in the U.S. patent literature is Example 11D of U.S. Pat. No. 3,819,637 (the ""637 patent). In Example 11 D, 6-HQ is prepared by cyclization of (p-metboxyphenyl)-3-chloropropionamide (xe2x80x9cMCPAxe2x80x9d). A blend of MCPA and AlCl3 was heated with rapid stirring to produce a melt and then further heated to 150xc2x0 C. and held at that temperature for half an hour. The melt was then poured into a slurry of cracked ice and hydrochloric acid to decompose the aluminum salts. 6-HQ was collected by filtration, washed with water and recrystallized from methanol. When these reaction conditions are scaled up, the high viscosity of the reaction medium causes temperature control problems. Cool regions form within the reactor and the 6-HQ and MCPA in those regions solidifies. Solidification hinders effective mixing of the reagents. Areas where high concentrations of AlCl3 are caused by inadequate mixing can become xe2x80x9chot spotsxe2x80x9d where thermal decomposition of the reactant and product occur.
When we repeated the ""637 process using 3 equivalents of AlCl3, the reaction did not go to completion and we obtained the intermediate product N-(4-hydroxyphenyl)-3-chloropropionamide (xe2x80x9cHPCAxe2x80x9d) in 28% yield. Though most of the HPCA could be removed by recrystallization from methanol as described in the ""637 patent, 6-HQ could not be obtained substantially free of contamination with HPCA. Reducing the amount of AlCl3 used in the reaction reduced the amount of HPCA but also reduced the overall yield of 6-HQ. The reaction time also increased; nevertheless, the rapidity of the melt process with either 2 or 3 equivalents of the catalyst is one of this method""s merits.
The ""637 process is a Friedel-Crafts alkylation. In contrast to Friedel-Crafts acylations, which have widespread utility, the usefulness of Friedel-Crafts alkylations is limited by a tendancy toward over-alkylation of the aromatic participant, low aromatic regioselectivity and the tendency of carbocation intermediates to rearrange. One of the most important uses of Friedel-Crafts alkylation is ring closure, which is less affected by these limitations than intermolecular reactions are. There is an xe2x80x9cintramolecular advantagexe2x80x9d associated with generating the carbocation on the same molecule as the aromatic ring. The half-life of the carbocation is decreased by the high local concentration of the reacting partner, which minimizes rearrangement to a more stable secondary carbocation.
Despite the intramolecular advantage, cyclization of MCPA is sluggish because the substitution must occur at a position on the aromatic ring ortho to an electron withdrawing group. An amido group bonded to an aromatic ring through its nitrogen atom, like the amide group in MCPA, is ordinarily a weak activator of the ring toward electrophilic aromatic substitution. However, in the cyclization of MCPA, the amide carbonyl coordinates with AlCl3. Coordination with AlCl3 converts the amide group into an electron withdrawing substituent and deactivates the aromatic ring toward electrophilic substitution. The deactivating effect of a Lewis acid on aromatic ketones has been described in Bull. Soc. Chim. Fr. 1984, 11, 285. In the ""637 patent, high temperatures and the highest concentration attainable, i.e. a melt, were used to drive the cyclization onto the deactivated ring of MCPA.
The ""637 patent also discloses in Example 11E a process for preparing the Friedel-Crafts starting material MCPA by adding 3-chloropropionyl chloride dropwise to a solution of p-anisidine in dry acetone.
Several investigators working in Japan have described modifications to the Friedel-Crafts reaction conditions of the ""637 patent.
According to Chemical Abstracts Doc. No. 127:34142, Japanese Patent No. 9-124605 describes an improved process in which the MCPA and AlCl3 are diluted with a liquid paraffin in mixture with either DMSO or an amide. Suitable amides in the JP ""605 process include N,N-dimethylformamide (xe2x80x9cDMFxe2x80x9d) and N,N-dimethylacetamide (xe2x80x9cDMAxe2x80x9d). A 76.9% yield of 6-HQ is reported after 20 h at 105xc2x0 C. in a mixture of paraffin and DMA. Suitable paraffins are C7-C14 hydocarbons. For a large scale process, the lower molecular weight hydrocarbons are preferable for economic reasons. As an example, one liter of the C7 hydrocarbon n-heptane costs less than a tenth as much of the C12 hydrocarbon dodecane.
In our hands and conducting the reaction in n-heptane and DMF at 100xc2x0 C., the yield was lower than claimed in the JP ""605 patent. The reaction also took longer but the purity of the product obtained after recrystallization from methanol and toluene was indeed improved over the ""637 process. As is apparent from the Chemical Abstract, this process suffers from a slow reaction rate.
According to Chemical Abstracts Doc. No. 133:585428, Japanese Patent No. 2000-229944, describes the AlCl3 catalyzed cyclization of MCPA in high boiling hydrocarbons like decahydronaphthalene and tetralin, and high boiling ethers like benzyl ethyl ether, isoamyl ether, diphenyl ether, diglyme and triglyme. Reaction of MCPA and AlCl3 for 8 h in decahydronaphthalene at 150xc2x0 C. gave 6-HQ in 90% yield. The JP ""944 patent also discloses a preparation of MCPA from p-anisidine and 3-chloropropionyl chloride in DMF, DMA, DMSO and diphenyl.
According to Chemical Abstracts Doc. No. 131:257448, Japanese Patent No. 11-269148 describes the Friedel-Crafts intramolecular alkylation of MCPA in a mixture of a halobenzene and an amide or amine. The reaction may be performed at between 110xc2x0 C. and 200xc2x0 C. with 0.1 to 10 equivalents of amine. It is reported that 6-HQ was obtained in 78% yield after fifteen hours at 130xc2x0 C. in a mixture o-dichlorobenzene and trioctylamine.
Aromatic solvents like benzene and tetralin are usually a poor solvent choice for conducting Friedel-Crafts alkylation reactions because the solvent, which is usually present in large excess, is susceptible to electrophilic attack. Halobenzenes like o-dichlorobenzene are somewhat deactivated towards electrophilic attack and, as mentioned, there is an intramolecular advantage favoring the Friedel-Crafts alkylation of MCPA. However, since the aromatic ring of MCPA is also deactivated, it was found that reaction with solvent was competitive with cyclization. The side products of reactions with solvent were detected as a complex pattern of peaks in the HPLC chromatogram of the product mixture that was absent from the chromatograms of the product mixtures from the melt and paraffin processes.
It would be desirable to have a process for making 6-HQ in a high level of purity, by a reaction that proceeds at a fast rate and with an improvement in the yield.
The present invention provides a process for preparing 6-hydroxy-3,4-dihydroquinolinone by intramolecular Friedel-Crafts alkylation of N-(4-methoxyphenyl)-3-chloropropionamide in which an equivalent of N-(4-methoxyphenyl)-3-chloropropionamide is contacted with about 3 to about 5 equivalents of a Lewis acid in DMSO or a high boiling amide or amine at an elevated temperature of from about 150xc2x0 C. to about 220xc2x0 C. A highly concentrated reaction mixture causes a fast reaction rate yet remains fluid throughout the reaction. The process produces 6-HQ in high yield and a high state of purity such that it may be used in subsequent reactions toward the preparation of cilostazol without intermediate purification. The present invention further provides a process for preparing cilostazol from 6-HQ prepared by the process. Improved processes for preparing N-(4-methoxyphenyl)-3-chloropropionamide are also provided.
The present invention provides an improved process for preparing 6-hydroxy-3,4-dihydroquinolinone (I) from N-(4-methoxyphenyl)-3-chloropropionamide (IV). The transformation from starting material to product involves a ring closure and a demethylation of the phenol group as depicted in Scheme 1. 
The present process is described using AMCl3 as catalyst, although other Lewis acids known to be useful for promoting Friedel-Crafts reactions like AlBr3, FeCl3, FeBr3, SbF5, TiCl4, SnCl4 and BF3 also may function effectively. The process uses from about 3 to about 5 molar equivalents of catalyst, preferably about 4 equivalents.
The reaction is conducted at high concentration in a diluent selected from the group consisting of DMSO, high boiling amines and high boiling N,N-disubstituted amides. Suitable amides and amines have boiling points in excess of 150xc2x0 C. so that the reaction may be conducted at ambient pressure without significant loss of the diluent by evaporation. Some evaporation is acceptable and the use of a vapor condensor with the reactor is recommended. High boiling N,N-disubstituted amides and amines that may be used include those previously described in Chemical Abstract Doc. Nos. 127:34142 and 131:257448, i.e. N,N-dimethyl formamide (xe2x80x9cDMFxe2x80x9d), N,N-dimethylacetamide (xe2x80x9cDMAxe2x80x9d) and octylamine and further include primary amines having C7 and higher formula weight alkyl or aryl substituents, secondary amines having C4 and higher formula weight alkyl or aryl substituents and tertiary amines having C4 and higher formula weight alkyl or aryl substituents. The most preferred diluent is DMA.
The diluent is added to the MCPA in an amount of from about 1 to about 1.3 equivalents, preferably about 1.3 equivalents. A solution in DMA accordingly has a molal concentration (moles solute/kg. solvent) of MCPA of from about 8.8 to about 11.5 molal. When 4 equivalents of AlCl3 is used as catalyst, this solution is from about 35.3 to about 45.9 molal in catalyst.
The reaction may be conducted at a temperature in the range of from about 150xc2x0 C. to about 220xc2x0 C., more preferably about 150xc2x0 C. to about 160xc2x0 C. Depending upon temperature, the reaction is substantially complete in 30 minutes to 2 hours. The reaction time is kept short by adding only an approximate molar equivalent of the diluent to the reaction mixture, which results in a highly concentrated reaction mixture.
The Friedel-Crafts cyclization obeys second order kinetics, consistent with a mechanism wherein the rate limiting step is the formation of the carbocation or MCPA-aluminum trichloride complex intermediate. The high rate of reaction and correspondingly short reaction time of the process are partly attributable to the high MCPA and AlCl3 concentration in the reaction mixture. This aspect of the invention would be lost by the addition of a paraffin, halogenated aromatic or high boiling ether, and thus neither these substances nor any others are added to the reaction in amounts that would increase the reaction time beyond about 3 hours. Another important aspect of the invention is that despite the high concentration, it is less prone to solidification due to variations in temperature at different locations within the reactor than a melt is. The diluents of this invention maintain the fluidity of the reaction mixture even at high concentration. As discussed below, a reaction mixture in DMA slurries as the reaction nears completion, but the slurry is easily stirred and does not cause hot spots.
The process is further illustrated with an illustrative step-wise description of the process in which the catalyst is AlCl3 and the solvent is DMA. The process may be performed in a reactor equipped with a heater, paddle stirrer, powder funnel, thermometer and vapor condensor. The reactor is charged with MCPA and 1.3 equivalents of DMA. The powder funnel is charged with 4 equivalents of AlCl3. AlCl3 is added slowly while stirring the cloudy mixture and monitoring the thermometer or reflux rate for excessive exotherm. Preferably, the temperature should not be allowed to exceed about 160xc2x0 C. during the addition. If a rapid exotherm occurs, control of the temperature may be regained by shutting off the flow of AlCl3 and allowing reflux to cool the reactor or by cooling the reactor externally. After completing the addition, progress of the reaction may be monitored by TLC (eluent: (12:8:2:2) MEK:CHCl3:CH2Cl2:IPA; Rf(6-HQ)=0.5). One indication that the reaction is nearing completion is that the mixture which originally was a slightly cloudy solution becomes a slurry. The slurry is easily stirred and does not contribute to hot spot formation in the reactor. The reaction typically takes another 30 minutes to 2 hours to go to completion after the addition of AlCl3 is complete.
The reaction may be quenched by slowly pouring the reaction mixture into aqueous or alcohol solution in a well ventilated area and then decomposing the aluminum salts with sodium borohydride and recovering 6-HQ by filtration. The aluminum salts also can be decomposed with hydrochloric acid.
The 6-HQ obtained by practicing the foregoing process may be used to prepare cilostazol by the novel method disclosed in U.S. patent application Ser. No. 09/929,683, which is hereby incorporated by reference in its entirety. The 6-HQ obtained by practicing the foregoing process also may be used to prepare cilostazol by other methods, such as the method described in U.S. Pat. No. 4,277,479, which is herein incorporated by reference for its teaching of the preparation of 3,4-dihydroquinolinone derivatives from 6-HQ. According to the ""479 patent""s method, 6-HQ is dissolved in ethanol containing DBU. 1-Cyclohexyl-5-(4-iodobutyl)-tetrazole is added dropwise to the refluxing solution over ninety minutes and the reaction mixture is refluxed for another 5 hours. The mixture is then concentrated and taken up in chloroform which is washed with dilute NaOH, dilute HCl and water. The organic phase is then dried over sodium sulfate and evaporated. The residue is recrystallized from an ethanol and water mixture to give cilostazol having a melting point of 148-150.5xc2x0 C.
The MCPA (IV) starting material for preparing 6-HQ may be prepared by improved acylation processes which produce MCPA in high yield and high purity, preferably in greater than 98% purity, which is suitable for use to prepare 6-HQ without chromatographic purification. Comparison of the results in Table 2 of the Examples shows that the following processes produce MCPA with purity comparable to the product obtained from the process of the ""637 patent but in a higher yield. The transformation from starting materials to product involves an acylation of p-anisidine with 3-chloropropionyl chloride as depicted in Scheme 2. 
The improvement over known processes for acylating p-anisidine with 3-chloropropionyl chloride resides in the base/solvent combinations used in the processes and the reaction conditions, particularly temperature, which provide the optimum yields and purity with the particular solvent/base combination.
In the most preferred of these processes, p-anisidine is dissolved in a sufficient amount of toluene to produce an approximately 3 to 5 M solution, more preferably about 4 M solution. Between 1 and 2 equivalents, more preferably about 1.5 equivalents, of sodium bicarbonate (xe2x80x9cNaHCO3xe2x80x9d) are suspended in the p-anisidine solution and the resulting suspension is stirred while an approximately equivalent amount 3-chloropropionyl chloride (i.e. 1-1.2 eq.) is added dropwise to the stirred suspension. The addition may be conducted at reduced or ambient temperature and the temperature may be allowed to rise, but should not be allowed to exceed 70xc2x0 C. After completing the addition, the temperature of the reaction is maintained at between room temperature and the reflux temperature of toluene (111xc2x0 C.), most preferrably about 60xc2x0 C., for a time sufficient for the reaction to be complete. Progress of the reaction may be monitored by TLC using the method described in Example 2a. After the reaction is complete, the reaction mixture is quenched with water or aqueous mineral acid and MCPA is isolated from the resulting suspension by filtration, decantation and the like, preferably filtration. The MCPA is then washed with water, toluene, or other nonviscous liquid in which the MCPA is not substantially soluble. The washed solid is then dried.
In another acylation process, N,N-dimethylformamide (xe2x80x9cDMFxe2x80x9d) fulfills the function of solvent and acid scavenger. p-Anisidine is dissolved in an amount of DMF to produce an approximately 2 to 3 M solution, more preferably about 2.7 M solution of p-anisidine in DMF. The from 1 to 1.2 equivalents of 3-chloropropionyl chloride are added to the solution. The reaction proceeds smoothly to completion in about 4 hours without external heating. MCPA may then be isolated from the reaction mixture by the method described with reference to the toluene/NaHCO3 process.
In an alternative acylation process which gives MCPA in high purity, albeit in lower yield than the toluene/NaHCO3 process, p-anisidine is dissolved in sufficient methyl ethyl ketone (xe2x80x9cMEKxe2x80x9d) to give an approximately 3 to 5 M solution, preferably about 4 M. Between 0.9 and 1.2 equivalents of triethyl amine (xe2x80x9cEt3Nxe2x80x9d) is added to the solution as acid scavenger followed by slow addition of between 0.9 and 1.2 equivalents of 3-chloropropionyl chloride. As previously described with reference to the toluene/NaHCO3 process, the addition may be conducted at reduced or ambient temperature and the temperature may be allowed to rise, but should not be allowed to exceed 70xc2x0 C. After completing the addition, the solution is refluxed (80xc2x0 C.) for a time sufficient to complete the reaction which may be determined by TLC using the method described in Example 2a. MCPA is then isolated from the reaction mixture as described with reference to the toluene/NaHCO3 process.
In yet another acylation process, p-anisidine is dissolved in sufficient dichioromethane to produce an approximately 2 to 4 M solution, more preferably about 3 M solution of p-anisidine. Approximately one equivalent of aqueous sodium hydroxide and approximately 0.9 to 1.7 equivalent of 3-chloropropionyl chloride are then added slowly and simultaneously to the solution so as to maintain an approximately neutral pH in the organic phase. The addition is preferrably performed at controlled low temperature of 0xc2x0 C. or less. The reaction may be quenched and the MCPA product may be isolated by the methods described with reference to the toluene/NaHCO3 process.